According to Cancer Facts & Figures. 2017 reported by the American Cancer Society, about 85% of lung cancers are non-small cell lung cancer (NSCLC), wherein 3%-5% of NSCLCs are anaplastic lymphoma kinase (ALK) positive.
Crizotinib is a drug for first-line treatment of ALK-positive NSCLC approved by the US Food and Drug Administration (FDA). The patients initially respond to crizotinib, while most patients develop drug resistance and relapse within 12 months. Therefore, more and more cancer patients need new and effective therapies for ALK positive cancer.
AP26113, also known as Brigatinib, is a targeted small molecule tyrosine kinase inhibitor developed by Ariad Pharmaceuticals Inc. for the treatment of patients with crizotinib-resistant ALK-positive NSCLC. The drug was designated as a breakthrough therapy by the FDA in August 2014 and was approved in the US on Apr. 28, 2017. Clinically, AP26113 has sustained anti-tumor activity in patients with ALK-positive NSCLC, including brain metastases patients. The chemical structure of AP26113 is shown in formula (I):

Different crystalline forms of drugs have different solubility and stability, which affect the absorption and bioavailability of drugs, leading to different clinical efficacy.
Patent application WO2016065028A1 reported crystalline forms of AP26113, including Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form J, Form K and Form L, wherein Form J, Form K and Form L are mixed crystals containing Form A; Form E, Form F, Form G and Form H are solvates which are not suitable for direct pharmaceutical use; Form C and Form D are hydrates; Form B is an anhydrate. Form B, Form C and Form D convert to each other under different humidity conditions, wherein Form B easily absorbs moisture and transforms to a hydrate; Form C and Form D can be easily dehydrated and transform to other forms. Therefore, only Form A is relatively stable. However, inventors of the present disclosure found that Form A has low solubility and slow dissolution rate, which is not conducive to fast release and efficient use of drugs. Therefore, it is necessary to perform further polymorph screening on AP26113 to find crystalline forms that are more suitable for development.
The inventors of the present disclosure unexpectedly discovered two novel crystalline forms of AP26113 suitable for drug development after a large number of experiments, named as Form CS1 and Form CS2. Form CS1 and Form CS2 of AP26113 provided by the present disclosure have advantages in solubility, stability, hygroscopicity and processability, especially in terms of solubility, Form CS1 and Form CS2 have better solubility and dissolution rate than Form A of the prior art. The discovery of Form CS1 and Form CS2 of the present disclosure provides a better choice for the preparation of pharmaceutical compositions containing AP26113 and is of great significance for drug development.